Viruses consist essentially of DNA or RNA in a protein coat. They have no ribosomes or protein-synthesizing apparatus, although some contain enzymes. They replicate by taking over the metabolic processes of the host. Because a virus virtually (and in some cases, actually) becomes part of its host cell, selective chemotherapy is difficult.
The human immunodeficiency virus (HIV) – an RNA retrovirus – will be taken as an example of viral infection of a host cell ( Fig. 29.1 ). Antiviral drugs will be dealt with under two headings: anti-HIV drugs and other antiviral agents.
Viral infection of a cell
The binding sites on the host cell to which the virus attaches are normal membrane constituents: receptors for cytokines, neurotransmitters or hormones, ion channels, integral membrane glycoproteins, etc. Thus the virus that causes infantile diarrhoea attaches to the β-adrenoceptor; the rabies virus attaches to the acetylcholine receptor on skeletal muscle. With many viruses, the receptor-virus complex enters the cell by receptor-mediated endocytosis during which the virus coat may be removed. Some viruses bypass this route.
On entering and infecting a host cell, the virus genome itself acts as – or is transcribed into – virus-specific messenger RNA, which then directs the synthesis of new virus particles. DNA viruses enter the host cell nucleus to accomplish this. Most RNA viruses replicate without involving the host cell nuclear material. RNA retroviruses (e.g. HIV, responsible for the acquired immunodeficiency syndrome (AIDS)) have an enzyme, reverse transcriptase, that makes a DNA copy of the viral RNA; this DNA copy is integrated into the host genome and directs the generation of new viral particles ( Fig. 29.1 ).
The two main groups of anti-HIV drugs are reverse transcriptase inhibitors (RTIs) and protease inhibitors. Combinations of these is essential in treatment to prevent the development of tolerance.
Reverse transcriptase inhibitors
Nucleoside RTIs (NRTIs) inhibit the action of the viral reverse transcriptase. The drugs are analogues of endogenous nucleosides and are phosphorylated by host cell enzymes to give a false 5’-trisphosphate. This competitively inhibits the equivalent trisphosphates of the host cell needed by the reverse transcriptase for the formation of the viral DNA. Examples are zidovudine , abacavir, didanosine, lamivudine, zalcitabine and stavudine.
Zidovudine (AZT, azidothymidine)
This analogue of thymidine is usually given orally but can be given by intravenous (IV) infusion. The cerebrospinal fluid (CSF) concentration is 65% of the blood level and the half-life of the false trisphosphate is 3 h. Most of the drug is metabolized in the liver, but 20% is excreted via the kidney. Unwanted effects with long-term use include blood dyscrasias, gastrointestinal (GI) tract disorders, central nervous system (CNS) disturbances, myopathy, rashes, fever and a flu-like syndrome. Short-term use in fit individuals usually causes only minor, reversible adverse effects. Resistance is likely to occur in late-stage HIV disease.
This guanosine analogue is given orally; it is well absorbed and inactivated in the liver. The CSF concentration is one-third that of the plasma. Unwanted effects include skin rashes, GI tract disturbances and, rarely, a serious general hypersensitivity reaction.
The non-nucleoside RTIs (NNRTIs) are chemically diverse compounds that denature the catalytic site of the reverse transcriptase. Examples are nevirapine and efavirenz.
This drug is given orally and its CSF concentration is 45% of that in the plasma. It is metabolized in the liver. Unwanted effects include rash and, rarely, Stevens–Johnson syndrome. Drug interactions can occur. This drug can reduce mother-to-child transmission of HIV by about 50%.
In the final stage of assembly and budding, a viral protease cleaves precursor polyproteins to give the structural and functional proteins of the new virions. Protease inhibitors prevent this step. Examples are saquinavir , indinavir and nelfinavir. All are given orally, saquinavir being subject to first-pass metabolism. All inhibit the P450 liver enzymes so drug interactions are possible. In general, these drugs are well tolerated. Unwanted effects include GI tract disturbances, insulin resistance and hyperlipidaemia. With long-term use, redistribution of fat is seen (some fat accumulation, some fat loss).